Cyclodextrins are known to form inclusion complexes with other molecules of suitable size and polarity (J. Pharm. Sci. 64, 1585; 1975). Cyclodextrins (or Schardinger dextrins) are cycloamyloses or cycloglucanes, cyclic oligosaccharides, the most significant representatives of which are .alpha.-cyclodextrin consisting of 6 anhydroglucopyranose units and .beta.-cyclodextrin consisting of 7 anhydroglucopyranose units. 1-(p-Chloro-benzoyl)-5-methoxy-2-methyl-indol-3-acetic acid (Indomethacin.sup.R) is a known antiinflammatory drug, but its disadvantage is its ulcerative effect (British Pat. No. 997.638). This compound shows further a protective effect during pregnancy.
We have now surprisingly found, that the inclusion complex of cyclodextrins with Indomethacin in a molar ratio of about 2:1 is free of the ulcerative side-effect and at the same time it exhibits entirely the same antiinflammatory activity and protective activity during pregnancy as Indomethacin.
The invention also provides a process for the preparation of the inclusion complex of cyclodextrin with indomethacin in a molar ratio of about 2:1 comprising reacting about 2 moles of .alpha.- or .beta.-cyclodextrin with 1 mole of 1-(p-chloro-benzoyl)-5-methoxy-2-methyl-indol-3-yl-acetic acid.
The interaction of cyclodextrins and indomethacin was investigated by Hamada, Nambu and Nagai (Chem. Pharm. Bull., 23, 1205; 1975). They observed, that by increasing the concentration of cyclodextrin in an aqueous solution, the solubility of Indomethacin is also increased. The original solubility could be increased from 3.5.times.10.sup.-4 moles/liter at 35.degree. C. to 9.8.times.10.sup.-4 moles/liter, i.e. the solubility was increased 2.8 times.
It has been disclosed, that Indomethacin in the presence of glucose hydrolyses rapidly in an aqueous solution, slowly in the presence of .alpha.-cyclodextrin and the .beta.-cyclodextrin inhibits hydrolysis.
Kurozumi, Nambu and Nagai (Chem. Pharm. Bull., 23, 3062; 1975) have tried to prepare the cyclodextrin-indomethacin complex. According to one attempt 100 ml. of a solution of 10.sup.-3 molar cyclodextrin was shaken at room temperature with 20 ml. of 3.times.10.sup.-3 molar ethereal indomethacin solution for 24 hours and the product was crystallized on cooling to 2.degree. C. The precipitated product, however, did not contain any Indomethacin but included pure .beta.-cyclodextrin. This has been explained in the mentioned article by saying that the hollow diameter of .beta.-cyclodextrin is only 7-8 A, while the diameter of the Indomethacin molecule is 8.5 A, i.e. it is too large to be incorporated into the hollow of .beta.-cyclodextrin.
There has also been an attempt to prepare the complex by lyophilization. Indomethacin was converted to an ammonium salt with 28% aqueous ammonium hydroxide; it was thus dissolved in water and an equimolar amount of .beta.-cyclodextrin was added in the form of an aqueous solution, the mixture was frozen and lyophilized. The obtained product contained both the starting indomethacin and cyclodextrin in the form of a mixture, i.e. a molar ratio of 1:1 (the molar ratio of Indomethacin: CD=0.92:1, according to the article). The authors referred to X-ray diffraction powder diagrams in order to prove that the 1:1 molar mixture is in fact a complex, but the diagrams have not been disclosed. X-ray diffraction powder diagrams of a complex obtained from ibufenac by crystallization and lyophilization have been disclosed in the article, and it can be seen, that the power diagram of the lyophilized .beta.-cyclodextrin and the powder diagram of the lyophilized ibufenac-.beta.-cyclodextrin complex are substantially identical, corresponding to an amorphous state. It is generally known that amorphous powders obtained by lyophilization do not show significant characteristics by X-ray diffraction powder exposure techniques. Takeo and Kuge (Agric. Biol. Chem., 34, 1787; 1970) report that .beta.-cyclodextrin inclusion complexes in an anhydrous dried state yield identical X-ray diffraction powder diagrams independently of the type of the complex-forming host molecule. The fact of the complex formation cannot be determined by means of X-ray diffraction data in case of lyophilized materials.
Consequently it was not the preparation of an Indomethacin-cyclodextrin complex that was disclosed in the above-mentioned article, but rather a physical mixture of the ammonium salt of Indomethacin and cyclodextrin as the product. According to our observations salts of Indomethacin cannot be incorporated in a cyclodextrin inclusion complex, the salts prove to be too ionic, i.e. hydrophilic.
The above mentioned Japanese authors set as an aim to prepare an 1:1 molar complex, but they did not succeed.